3,7 or 3 and 7 thia or oxa prostanoic acid derivatives as agents for lowering intraocular pressure

ABSTRACT

The present invention provides a method of treating ocular hypertension or glaucoma which comprises administering to an animal having ocular hypertension or glaucoma a therapeutically effective amount of a 3, 7 or 3 and 7 thia or oxa prostanoic acid derivative.

FIELD OF THE INVENTION

The present invention relates to 3, 7 or 3 and 7 thia or oxa prostanoicacid derivatives as potent ocular hypotensives that are particularlysuited for the management of glaucoma.

BACKGROUND OF THE INVENTION Description of Related Art

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical b-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives have been reported to possessocular hypotensive activity, and have been recommended for use inglaucoma management. Eicosanoids and derivatives include numerousbiologically important compounds such as prostaglandins and theirderivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

Prostaglandins were earlier regarded as potent ocular hypertensives,however, evidence accumulated in the last decade shows that someprostaglandins are highly effective ocular hypotensive agents, and areideally suited for the long-term medical management of glaucoma (see,for example, Bito, L. Z. Biological Protection with Prostaglandins,Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252;and Bito, L. Z., Applied Pharmacology in the Medical Treatment ofGlaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune &Stratton, 1984, pp. 477-505. Such prostaglandins include PGF_(2α),PGF_(1α), PGE₂, and certain lipid-soluble esters, such as C₁ to C₂ alkylesters, e.g. 1-isopropyl ester, of such compounds.

Although the precise mechanism is not yet known experimental resultsindicate that the prostaglandin-induced reduction in intraocularpressure results from increased uveoscleral outflow [Nilsson et.al.,Invest. Ophthalmol. Vis. Sci. (suppl), 284 (1987)].

The isopropyl ester of PGF_(2α) has been shown to have significantlygreater hypotensive potency than the parent compound, presumably as aresult of its more effective penetration through the cornea. In 1987,this compound was described as “the most potent ocular hypotensive agentever reported” [see, for example, Bito, L. Z., Arch. Ophthalmol. 105,1036 (1987), and Siebold et.al., Prodrug 5 3 (1989)].

Whereas prostaglandins appear to be devoid of significant intraocularside effects, ocular surface (conjunctival) hyperemia and foreign-bodysensation have been consistently associated with the topical ocular useof such compounds, in particular PGF_(2α) and its prodrugs, e.g., its1-isopropyl ester, in humans. The clinical potentials of prostaglandinsin the management of conditions associated with increased ocularpressure, e.g. glaucoma are greatly limited by these side effects.

In a series of co-pending United States patent applications assigned toAllergan, Inc. prostaglandin esters with increased ocular hypotensiveactivity accompanied with no or substantially reduced side-effects aredisclosed. The co-pending U.S. Ser. No. 596,430 (filed Oct. 10, 1990,now U.S. Pat. No. 5,446,041), relates to certain 11-acyl-prostaglandins,such as 11-pivaloyl, 11-acetyl, 11-isobutyryl, 11-valeryl, and11-isovaleryl PGF_(2α). Intraocular pressure reducing 15-acylprostaglandins are disclosed in the co-pending application U.S. Ser. No.175,476 (filed Dec. 29, 1993). Similarly, 11,15- 9,15 and 9,11-diestersof prostaglandins, for example 11,15-dipivaloyl PGF_(2α) are known tohave ocular hypotensive activity. See the co-pending patent applicationsU.S. Ser. No. 385,645 (filed Jul. 7, 1989, now U.S. Pat. No. 4,994,274),U.S. Ser. No. 584,370 (filed Sep. 18, 1990, now U.S. Pat. No. 5,028,624)and U.S. Ser. No. 585,284 (filed Sep. 18, 1990, now U.S. Pat. No.5,034,413). The disclosures of all of these patent applications arehereby expressly incorporated by reference.

Certain 3, 7 dithiaprostanoic acid derivatives are disclosed in thefollowing patents which are hereby incorporated by reference in theirentirety. U.S. Pat. No. 6,043, 275 to Maruyama et al; U.S. Pat. No.5,892,099 to Maruyama et al; EP 0 855 389; EP 0 985 663; Japanese PatentPublication 2000-1472 and Japanese Patent Publication 10-265454.

SUMMARY OF THE INVENTION

The present invention concerns a method of treating ocular hypertensionwhich comprises administering to a mammal having ocular hypertension atherapeutically effective amount of a compound of formula I

wherein hatched lines represent the α configuration, a trianglerepresents the β configuration and a dotted line represents the presenceor absence of a double bond;

A and B are independently selected from the group consisting of O, S andCH₂, provided that at least one of A or B is S;

D represents a covalent bond or CH₂, O, S or NH;

X is CO₂R, CONR₂, CH₂OR, P(O)(OR)₂, CONRSO₂R, SONR₂ or

Y is O, OH, OCOR², halogen or cyano;

Z is CH₂ or a covalent bond;

R is H or R²;

R¹ is H, R²,phenyl, or COR²;

R² is C₁-C₅ lower alkyl and R³ is C₁-C₅ n-alkyl, C₃-C₇ cycloalkyl,phenyl, furanyl, thienyl, or substituted derivatives thereof, whereinthe substituents maybe selected from the group consisting of C₁-C₅alkyl, halogen, CF₃, CN, NO₂, NR₂, CO₂R and OR.

In a still further aspect, the present invention relates to apharmaceutical product, comprising

a container adapted to dispense its contents in a metered form; and

an ophthalmic solution therein, as hereinabove defined.

Finally, certain of the compounds represented by the above formula,disclosed below and utilized in the method of the present invention arenovel and unobvious.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIG. 1 is a schematic of the chemical synthesis of a certainintermediate useful in the chemical synthesis of certain of thecompounds of the invention.

FIG. 2 is a schematic of the chemical synthesis of certain compounds ofthe invention as disclosed in Examples 5 through 7.

FIG. 3 is a schematic of the chemical synthesis of certain compounds ofthe invention as disclosed in Examples 9 and 10.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of 3, 7 or 3 and 7 thia or oxaprostanoic acid derivatives as ocular hypotensives. The compounds usedin accordance with the present invention are encompassed by thefollowing structural formula I:

A preferred group of the compounds of the present invention includescompounds that have the following structural formula II:

Another preferred group includes compounds having the formula III:

In the above formulae, the substituents and symbols are as hereinabovedefined.

In the above formulae:

Preferably A and B are both S.

Preferably D represents a covalent bond or is CH₂.

Preferably R is H.

Preferably R¹ is H.

Preferably when D represents a covalent bond, R³ is n-butyl or 1-propylcyclobutyl.

Preferably Y=O.

Preferably X is CO₂R and more preferably R is selected from the groupconsisting of H, methyl and i-propyl.

The above compounds of the present invention may be prepared by methodsthat are known in the art or according to the working examples below.The compounds, below, are especially preferred representative, of thecompounds of the present invention.

{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl-sulfanyl]propylsulfanyl}aceticacid methyl ester.

{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl-sulfanyl]propylsulfanyl}aceticacid.

{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl-sulfanyl]propylsulfanyl}aceticacid isopropyl ester.

(3-{(1R,2S,3R)-3-Hydroxy-2-[(E)-4-hydroxy-4-(1-propylcyclobutyl)but-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid methyl ester.

(3-{(1R,2S,3R)-3-Hydroxy-2-[(E)-4-hydroxy-4-(1-propylcyclobutyl)but-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid.

Pharmaceutical compositions may be prepared by combining atherapeutically effective amount of at least one compound according tothe present invention, or a pharmaceutically acceptable acid additionsalt thereof, as an active ingredient, with conventional ophthalmicallyacceptable pharmaceutical excipients, and by preparation of unit dosageforms suitable for topical ocular use. The therapeutically efficientamount typically is between about 0.0001 and about 5% (w/v), preferablyabout 0.001 to about 1.0% (w/v) in liquid formulations.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 6.5 and 7.2with an appropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. The preferred chelating agent isedentate disodium, although other chelating agents may also be used inplace or in conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10 pH adjustorq.s. pH 4.5-7.5 antioxidant as needed surfactant as needed purifiedwater as needed to make 100%

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The ophthalmic formulations of the present invention are convenientlypackaged in forms suitable for metered application, such as incontainers equipped with a dropper, to facilitate the application to theeye. Containers suitable for dropwise application are usually made ofsuitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution.

The invention is further illustrated by the following non-limitingExamples, which are summarized in the reaction schemes of FIGS. 1through 3 wherein the compounds are identified by the same designator inboth the Examples and the Figures.

EXAMPLE 1 (R)-4-(tert-Butyldimethylsilanyloxy)cyclopent-2-enone (2)

Tetrapropylammonium perruthenate (9.4 mg, 0.027 mmol) was added to amixture of (1S, 4R)-4-(tert-butyldimethylsilanyloxy)cyclopent-2-enolprepared, according to Tetrahedron Letters, Vol. 37, No. 18, 1996, pp.3083-6, (118.6 mg, 0.54 mmol), 4-methylmorpholine N-oxide (94.9 mg, 0.81mmol) and crushed 4Å sieves (270 mg) in CH₂Cl₂ (10 mL). The mixture wasstirred for 30 min and was passed through a plug of silica gel withCH₂Cl₂. The filtrate was concentrated in vacuo to give 100 mg (86%) ofthe above titled compound.

EXAMPLE 2(R)-4-(tert-Butyldimethylsilanyloxy)-6-oxabicyclo[3.1.0]hexan-2-one (3)

Hydrogen peroxide (4.5 mL, 46.3 mmol, 30% by wt.) and 1N NaOH (46 μL,0.046 mmol) were added to a solution of enone 2 (2.5 g, 11.5 mmol) inMeOH (30 mL) at 0° C. After stirring 1.5 h at 0° C. the mixture wasconcentrated in vacuo, washed with saturated aqueous NH₄Cl and extractedwith CH₂Cl₂ (3×). The combined organics were washed with brine, dried(Na₂SO₄), filtered and concentrated in vacuo to afford the above titledcompound.

EXAMPLE 3({3-[(R)-3-(tert-Butyldimethylsilanyloxy)-5-oxocyclopent-1-enylsulfanyl]propyl-sulfanyl}aceticacid methyl ester (5)

The epoxide 3 prepared above was diluted with CH₂Cl₂ (30 mL),(3-mercaptopropylsulfanyl) acetic acid methyl ester 4 (1.93 g, 10.7mmol), prepared according to Chem. Pharm. Bull. 28 (2), 1980, 558-566,was added and the solution was cooled to 0° C. Basic alumina (11.9 g)was added and the reaction mixture was warmed to room temperature. Afterstirring for 18 h the mixture was filtered through celite andconcentrated in vacuo. The residue was purified by flash columnchromatography (silica gel, 6:1 hex/EtOAc) to yield 3.6 g (80%) of theabove titled compound.

EXAMPLE 4(3{(1R,2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[(S)-(E)-3-(tert-butyldimethylsilanoxy)oct-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)acetic acid methyl ester (7)

tert-Butyllithium (1.47 mL of a 1.7M solution in pentane, 2.5 mmol) wasadded dropwise to a solution of tert-butyl[(S)-1-((E)-2-iodovinyl)hexyloxy]dimethylsilane 6 (462.5 mg, 1.25 mmol) in Et₂O (6.0 mL) at −78°C. After stirring for 30 min lithium 2-thienylcyanocuprate (6.0 mL of a0.25M solution in THF, 1.5 mmol) was added and the reaction was stirredan additional 30 min at −78° C. A solution of enone 5 (430 mg, 1.1 mmol)in Et₂O (1 mL) was added and stirring was continued for an additional 1h. The reaction mixture was then quickly poured into saturated aqueousNH₄Cl cooled to 0° C. The mixture was extracted with EtOAc and theorganic portion was washed with brine, dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was quickly purified by flash columnchromatography (silica gel, 100% hexane followed by 8:1 hex/EtOAc) toafford 270 mg (39%) of the above titled compound.

EXAMPLE 5{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl-sulfanyl]propylsulfanyl}aceticacid methyl ester (8)

Hydrogen fluoride-pyridine (220 μL) was added to a solution of bis-TBDMSether 7 (70 mg, 0.11 mmol) in CH₃CN (2.0 mL) at 0° C. The reaction waswarmed to room temperature, stirred 1 h, and recooled to 0° C. Thereaction was quenched with saturated aqueous NaHCO₃ until gas evolutionceased. The mixture was extracted with CH₂Cl₂ (4×). The combinedorganics were washed with brine, dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography (silica gel, 100% CH₂Cl₂ followed by 30:1 CH₂Cl₂:MeOH)provided 40 mg (90%) of the above titled compound.

EXAMPLE 6{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl-sulfanyl]propylsulfanyl}aceticacid (9)

Methyl ester 8 (50 mg, 0.124 mmol) was dissolved in CH₃CN (10 μL) and pH7.2 phosphate buffer (3.0 mL) was added. The mixture was treated withPLE (400 μL, 1.34 μmol/μL) and stirred for 16 h at 23° C. The reactionmixture was extracted with EtOAc (3×). The combined organics were washedwith brine, dried (Na₂SO₄), filtered and concentrated in vacuo.Purification of the residue by flash column chromatography (silica gel,100% EtOAc) gave 5.3 mg (11%) of the above titled compound.

EXAMPLE 7{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-5-oxocyclopentyl-sulfanyl]propylsulfanyl}aceticacid isopropyl ester (10)

Isopropyl-p-tolyltriazene (200 μL) was added dropwise to a solution ofcarboxylic acid 9 (10.5 mg, 0.026 mmol) in acetone (5.0 mL) at 23° C.After stirring for 1 h the reaction was quenched with 1N HCl and thesolvent was removed in vacuo. The residue was extracted with CH₂Cl₂(2×). The combined organics were dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography (silica gel, 4:1 hex/EtOAc) gave 4.3 mg (38%) of theabove titled compound.

EXAMPLE 8(3-{(1R,2S,3R)-3-(tert-Butyldimethylsilanyloxy)-2-[(E)4-(tert-butyldimethyl-silanoxy)4-(1-propylcyclobutyl)but-1-enyl]-5-oxocyclopentylsulfanyl}propyl-sulfanyl)aceticacid methyl ester (12)

According to the procedure described above in Example 4,150 mg (29%) ofthe above titled compound was prepared employing enone 5 (303 mg, 0.775mmol) andtert-butyl-[(E)4-iodo-1-(1-propylcyclobutyl)but-3-enyloxy]dimethylsilane11 (328 mg, 0.777 mmol).

EXAMPLE 9(3-{(1R,2S,3R)-3-Hydroxy-2-[(E)4hydroxy4-(1-propylcyclobutyl)but-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid methyl ester (13)

According to the procedure described above in Example 5,7.9 mg (40%) ofthe above titled compound was prepared from enone 12 (30 mg, 0.045mmol).

EXAMPLE 10(3-{(1R,2S,3R)-3-Hydroxy-2-[(E)-4hydroxy-4-(1-propylcyclobutyl)but-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid (14)

According to the procedure described above in Example 6,4.1 mg (42%) ofthe above titled compound was prepared from ester 13 (10 mg, 0.023mmol).

The effects of the compounds of this invention on intraocular pressureare also provided in the following tables. The compounds were preparedat the said concentrations in a vehicle comprising 0.1% polysorbate 80and 10 mM TRIS base. Dogs were treated by administering 25 μl to theocular surface, the contralateral eye received vehicle as a control.Intraocular pressure was measured by applanation pneumatonometry. Dogintraocular pressure was measured immediately before drug administrationand at 6 hours thereafter.

Compounds 9 and 10 were examined and showed a pronounced ocularhypotensive effect in dogs and the glaucomatous cynomonlgus monkeys,respectively. Compound 9 at a dose of 0.1% w/v reduced the intraocularpressure (IOP) by 50% and at a dose of 0.01% w/v reduced the IOP by 45%.

Compound 10 at a dose of 0.01% w/v reduced the IOP in the glaucomatouscynomonlgus monkey.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

What is claimed is:
 1. A method of treating ocular hypertension orglaucoma which comprises administering to an animal having ocularhypertension or glaucoma a therapeutically effective amount of acompound represented by the general formula I;

wherein hatched lines represent the α configuration, a trianglerepresents the β configuration and a dotted line represents the presenceor absence of a double bond; A and B are independently selected from thegroup consisting of O, S and CH₂, provided that at least one of A or Bis S; D represents a covalent bond or CH₂, O, S or NH; X is CO₂R, CONR₂,CH₂OR, P(O)(OR)₂, CONRSO₂R, SONR₂ or

Y is O, OH, OCOR², halogen or cyano; Z is CH₂ or a covalent bond; R is Hor R²; R¹ is H, R², phenyl, or COR²; R² is C₁-C₅ lower alkyl and R₃ isC₁-C₅ n-alkyl, C₃-C₇ cycloalkyl, phenyl, furanyl, thienyl, orsubstituted derivatives thereof, wherein the substituents maybe selectedfrom the group consisting of C₁-C₅ alkyl, halogen, CF₃, CN, NO₂, NR₂,CO₂R and OR.
 2. The method according to claim 1 wherein said compound isrepresented by the general formula II;


3. The method according to claim 2 wherein said compound is representedby the general formula III;


4. The method of claim 1 wherein A and B are both S.
 5. The method ofclaim 1 wherein D represents a covalent bond or is CH₂.
 6. The method ofclaim 1 wherein X is CO₂R.
 7. The method of claim 6 wherein R isselected from the group consisting of H, methyl and i-propyl.
 8. Themethod of claim 1 wherein R is H.
 9. The method of claim 1 wherein R₁ isH.
 10. The method of claim 1 wherein D represents a covalent bond. 11.The method of claim 10 wherein R³ is n-butyl or 1-propylcyclobutyl. 12.The method of claim 1 wherein said compound is selected from the groupconsisting of{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid methyl ester,{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid,{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid isopropyl ester,(3-{(1R,2S,3R)-3-Hydroxy-2-[(E)-4-hydroxy-4-(1-propylcyclobutyl)but-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid methyl ester, and(3-{(1R,2S,3R)-3-Hydroxy-2-[(E)-4-hydroxy-4-(1-propylcyclobutyl)but-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid.
 13. An ophthalmic solution comprising a therapeutically effectiveamount of a compound represented by the general Formula 1

wherein hatched lines represent the α configuration, a trianglerepresents the β configuration and a dotted line represents the presenceor absence of a double bond; A and B are independently selected from thegroup consisting of O, S and CH₂ provided that at least one of A or B isS; D represents a covalent bond or CH₂ , O, S or NH; X is CO₂R, CONR₂,CH₂OR, P(O)(OR)₂, CONRSO₂R SONR₂ or

Y is O, OH, OCOR², halogen or group; Z is CH₂ or a covalent bond; R is Hor R²; R¹ is H, R² , phenyl, or COR²; R² is C₁-C₅ lower alkyl and R₃ isC₁-C₅ n-alkyl, C₃-C₇ cycloalkyl, phenyl, furanyl, thienyl, orsubstituted derivatives thereof, wherein the substituents maybe selectedfrom the group consisting of C₁-C₅ alkyl, halogen, CF₃, CN, NO₂, NR₂,CO₂R and OR in admixture with a non-toxic, ophthalmically acceptableliquid vehicle, packaged in a container suitable for meteredapplication.
 14. A pharmaceutical product, comprising a containeradapted to dispense the contents of said container in metered form; andan ophthalmic solution according to claim 13 in said container.
 15. Anovel compound selected from the group consisting of{3-[(1R,2S,3R)-3-Hydroxy-2-((S)-(E)-3-hydroxyoct-1-enyl)-5-oxocyclopentylsulfanyl]propylsulfanyl}aceticacid isopropyl ester (10).(3-{(1R,2S,3R)-3-Hydroxy-2-[(E)-4-hydroxy-4-(1-propylcyclobutyl)but-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid methyl ester (13) and(3-{(1R,2S,3R)-3-Hydroxy-2-[(E)-4-hydroxy-4-(1-propylcyclobutyl)but-1-enyl]-5-oxocyclopentylsulfanyl}propylsulfanyl)aceticacid (14).